Treatment and prevention of gastrointestinal disease using antagonists or partial agonists of 5HT1a receptors

ABSTRACT

The present invention provides a method for preventing and treating gastrointestinal diseases such as dyspepsia, irritable bowel disease and chemotherapy associated nausea by administering an antagonist or partial agonist of 5HT1A receptors.

This application claims the priority of Provisional Application60/161,117 filed Oct. 22, 1999.

FIELD OF THE INVENTION

The present invention provides a method for preventing and treatinggastrointestinal diseases such as dyspepsia, irritable bowel disease andchemotherapy-associated nausea by administering an antagonist or partialagonist of 5HT1a receptors.

BACKGROUND OF THE INVENTION

Dyspepsia is a common symptom ranging in prevalence from 26% in theUnited States to 41% in England (1). Whilst only 1 in 4 patients seekmedical help (2) the condition results in significant health care costs(3) and an organic cause is found in only 40% of patients. The Romecriteria for diagnosing idiopathic or nonulcer dyspepsia (NUD) were putforward in 1991 and consist of chronic or recurrent upper abdominal painor discomfort in the absence of obvious pathology (4). The Rome groupsuggested subcategorising NUD into ulcer-like, reflux-like,dysmotility-like and non-specific dyspepsia. This classification hasbeen questioned on the grounds that there is a marked overlap ofsymptoms and an overlap between the symptoms and those of the irritablebowel syndrome (5).

Conventional diagnostic evaluation (endoscopy, ultrasonography, 24 hambulatory pH monitoring) does not reveal a structural or biochemicalabnormality to explain NUD Attempts at elucidating the pathophysiologyof the condition have produced inconsistent findings (6) and a widearray of theories are currently put forward (7).

Serotonin (5HT) is a neurotransmitter both in the enteric nervous system(8) and in the brain (9). It plays a key role in regulating gutphysiology, including peristalsis and intestinal tone (10). Animalstudies have shown that intracerebroventricular injection offenfluramine (a serotonin releasing agent) inhibits gastric emptying(11). Selective serotonin reuptake inhibitors, such as fluoxetine andsertraline, are widely used in the treatment of depression and produce atransient syndrome similar to NUD in up to 30% of patients treated (12).

Studies indicate that a central 5HT1a receptor hypersensitivity may beinvolved in the pathophysiology of NUD (13,14). The release of prolactinfrom the anterior pituitary is under dopamine inhibition and under 5HTstimulation, probably at the level of the hypothalamus (15). Buspironeis an azaspirodecanedione, which acts as a partial agonist at the 5HT1areceptor (16) and stimulates prolactin release. We have established thatprolactin release following buspirone challenge is enhanced in NUDindicating 5HT1a receptor supersensitivity in this condition.

We have demonstrated this in a clinical study that extends our previousfindings reported in U.S. Pat. No. 5,403,848.

A total of 109 subjects, 50 NUD patients (39 female/11 male) and 59healthy comparison subjects (32 female/28 male) gave fully informedconsent to take part in the study, which had Ethics Committee approval.The mean±SD age of the patients was 35.6±12.2 years (Range 20-62) and ofthe comparison group 27.2±7.6 years (Range 20-52). At 0830 h subjectshad a cannula inserted in a forearm vein. Buspirone (30 mg) or matchingplacebo was administered orally at 0900 h (Time 0). Blood was taken at0, 30, 60. 90, 120 and 180 min. Prolactin levels rose in all subjectschallenged with buspirone. The mean±SD AUC in patients was 46±35 and inhealthy subjects 24±35. A 2-way repeated measures ANOVA yields asignificant group X time interaction, with differences significant at 60min (p<0.05), 90 min (p<0.01) and 120 min (p<0.05). Prolactinconcentration at 90 min provided the best discrimination between the twogroups.

According to the present invention, what is required to treatnon-ulcerative dyspepsia is the administration of effective amounts of asubstance that reduces the sensitivity of 5HT1a receptors and we havediscovered that pindolol, which has affinity for 5HT1a receptors hasbeneficial effects in subjects suffering from non-ulcerative dyspepsia.

SUMMARY OF THE INVENTION

The present invention provides a means for prevention and treatment ofgastrointestinal disease by administration of a substance that reducesthe sensitivity of 5HT1a receptors. A preferred means is theadministration of RS pindolol or a salt thereof. An especially preferredmeans is the administration of S (−) pindolol or a salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

As noted earlier, this invention can use any substance that is anantagonist or a partial agonist of 5HT1a receptors such that thesensitivity of 5HT1a receptors described above is reduced.

Pindolol is a beta adrenergic antagonist, used in the treatment ofhypertension and angina. It also has affinity for 5HT1a receptors of asimilar magnitude as its affinity for beta adrenergic receptors. Untilnow, no therapeutic applications of this phenomenon have beendiscovered. Pindolol is used therapeutically in hypertension and anginaas the racemic substance, RS pindolol. Most or all of thepharmacological effects of pindolol are possessed by the isomer S (−)pindolol. The present invention utilizes pindolol to reduce thesensitivity of 5HT1a receptors and as a result to provide the means forprevention and treatment certain gastrointestinal diseases, includingnon-ulcerative dyspepsia. A preferred embodiment of the invention is theisomer S (−) pindolol or salts thereof. Another method utilizes theadministration of cyproheptadine, described in U.S. Pat. Nos. 5,324,738and 5,403,848. The latter also describes a method for diagnosis ofnon-ulcerative dyspepsia by measuring the responsiveness of 5HT1areceptors. RS pindolol has an advantage over cyproheptadine of greaterselectivity for the 5HT1a receptor and S (−) pindolol has furtheradvantages of greater potency and specificity.

The invention is likely to be effective in various presentations ofgastrointestinal disease in which there is altered sensitivity of 5HT1areceptors. We have specific demonstration of the role of 5HT1a receptorsin non-ulcerative dyspepsia, but there is likely to be also benefit incertain cases of irritable bowel syndrome, especially that occurring inthe upper intestinal region and in certain cases of motility disorders(including nausea) caused by cancer chemotherapy.

Various pharmaceutical presentations are possible, including (but notlimited to) tablets, capsules, oral solutions and suspensions andparenteral solutions. Included are also pharmaceutical formulations fororal use in which the active substance is released in a controlled andslower fashion such that the treatment may be administered lessfrequently.

The usual doses of RS pindolol and S (−) pindolol will be in the rangeof 2.5 mg to 50 mg daily in single or divided doses, depending upon thetherapeutic response and the pharmaceutical form. The usual doses of S(−) pindolol will be lesser than those of RS pindolol since the formerwill be more potent because it is responsible for most or all of thepharmacological effects.

The invention is intended for the treatment of mammals, includinghumans.

The ability of the invention to treat gastrointestinal disease has beendemonstrated in a clinical study.

EXAMPLE

Eleven patients suffering from non-ulcerative dyspepsia were recruitedto a clinical study and gave informed consent. All were treated withpindolol 2.5 mg three times daily. Seven of the 11 patients showed asignificant improvement in symptoms within 1 week of commencingtreatment. A further patient improved in the second week. Theirresponses were quantified using a standard rating scale (GSRS scores).The results demonstrated a substantial improvement with a reduction inaverage symptom severity of approximately 68% in three weeks, with thegreatest improvement observed within one week. TABLE 1 Mean symptomscore (average of 11 patients) Week Mean GSRS Score 0 9 1 4.2 2 3.5 32.9

REFERENCES TO PREVIOUS PATENTS

T. G. Dinan and P. W. N. Keeling U.S. Pat. No. 5,324,783

T. G. Dinan and P. W. N. Keeling U.S. Pat. No. 5,403,848

OTHER REFERENCES

1. Fisher R S, Parkman H P. Management of nonulcer dyspepsia. N Engl JMed 1998; 339:13-6-81.

2. Brown C, Rees E W E. Dyspepsia in general practice. BMJ 1990;300:829-30.

3. Nyren O, Adami H O, Gustavsson S, Loof L. Excess sick-listing innonulcer dyspepsia. J Clin Gastroenterol 1986; 8:339-45.

4. Talley N J, Colin-Jones D, Koch K I, Koch M, Nyren O, StranghelliniV. Functional dyspepsia: a classification with guidelines of diagnosisand management. Gastroenterol Int 1991; 4:145-60.

5. Talley N J, Zinsmeister A R, Schleck C D, Melton L J. Dyspepsia anddyspepsia subgroupings: a population-based study. Gastroenterology 1992;102:1259-68.

6. Talley N J, Philips S F. Non-ulcer dyspepsia: potential causes andpathophysiology. Ann Intern Med 1988; 108:865-79.

7. Dotevall G. Psychosomatic gastroenterology today and some ideas fortomorrow. Gastroenterol Int 1989; 2:96-100.

8. Gershon M D. Erde S M. The nervous system of the gut.Gastroenterology 1981; 80; 1571-94.

9. Baumagarten H G, Grozdanovic Z. Neuroanatomy and neurophysiology ofcentral serotonergic systems. J Serotonin Res 1994; 1:171-81.

10. Lundgren O, Svanvik J, Jivegard L. Enteric nervous system: 1.Physiology and pathophysiology of the intestinal tract. Digest Dis Sci1989; 34:264-83.

11. Rowland N, Carlton J. Inhibition of gastric emptying by peripheraland central fenfluramine in rats: correlation with anorexia. Life Sci1984; 34:2495-9.

12. Thakore J H, Berti C, Dinan T G. Treating depression with specificserotonergic acting agents. J Serotonin Res 1996; 3:145-160.

13. Dinan T G, Yatham L N, Barry S, Chua A, Keeling P W N. Serotoninsupersensitivity: the pathophysiologic basis of non-ulcer dyspepsia? Apreliminary report of buspirone/prolactin responses. Scand JGastroenterol 1990; 25:541-44.

14. Chua K, Keating J, Hamilton D, Keeling P W N, Dinan T G, Centralserotonin receptors and delayed gastric emptying in in-ulcer dyspepsia.BMJ 1992; 305:280-2.

15. Lamberts S W J, Macleod R M. Regulation of prolactin secretion atthe level of the lactrotroph. Physiol Rev. 1990; 70:279-318.

16. Meltzer H Y, Maes M. Effects of buspirone on plasma prolactin andcortisol levels in major depressed and normal subjects. Biol Psychiat.1994; 35:316-323.

1. A method for preventing and treating gastrointestinal disease bymeans of administration of an effective amount of an antagonist orpartial agonist of 5HT1a receptors.
 2. A method according to claim 1employing an effective amount of the racemic substance RS pindolol or asalt thereof.
 3. A method according to claim 1 employing an effectiveamount of one of the enantiomers, S (−) pindolol of claim 2 or a saltthereof.
 4. A method according to claim 1 in which effective amounts ofRS-pindolol or S(−) pindolol or their salts are administered in apharmaceutical dosage form that permits rapid release of the activesubstances.
 5. A method according to claim 1 in which effective amountsof RS pindolol or S(−) pindolol or their salts are administered in apharmaceutical dosage form that releases the active substances in a slowor controlled fashion that in turn permits administration of the activesubstances at lesser frequency than in claim
 4. 6. A method according toclaim 1 in which the gastrointestinal diseases are characterised asnon-ulcerative dyspepsia or irritable bowel syndrome orchemotherapy-associated disorders of motility, including nausea.